7 Nov 2017 FDA VRBPAC: Pfizer’s S. aureus vaccine — do results in one population generalize? (Part 2 of 3)

Addendum: This is the second in a 3-newsletters series on this topic. Go here for the first newsletter and here for the final newsletter. Finally, the results of the STRIVE trial have been published as Hassanzadeh et al. in Clinical Infectious Diseases, ciad218, https://doi.org/10.1093/cid/ciad218.

Dear All: 

wrote on 19 Oct 2017 about the meeting on 7 Nov 2017 of the Vaccines and Related Biological Products Committee (VRBPAC) at White Oak to discuss Pfizer’s investigational Staphylococcus aureus vaccine intended for pre-surgical prophylaxis in elective orthopedic surgical populations. I noted before, we’ve had prior debates on this topic that have revolved around these questions:

  1. Can you use eradication of carriage as a measure of the value of prophylactic agent?
  2. How big does the study have to be if you must show reduction in a serious (non-trivial) clinical infection?
  3. In what population can you do this?

As I indicated previously, the answers to these questions to date have been NO, VERY LARGE, and NOT SURE.  A briefing book by FDA is now posted online and allows us to see under the hood. In brief, the VRPBAC will focus on the problem of questions (2) and (3) from above as follows:

  1. Pfizer have initiated a Phase 3 trial of their vaccine in a population with the highest rate of surgical infection (despite good care) they could find: open, posterior approach, multi-level, instrumented, spinal fusion orthopedic surgery.
  2. The post-op infection rate in this population is 1.4%. Based on this, Pfizer have been running a trial that (per clinicaltrials.gov) will enroll over 3 years about 2,600 subjects at 1:1 vaccine:placebo.
  3. Per the briefing book, Pfizer estimate this sample size gives them an 88% power to detect a 70% (or better) reduction in post-op infection rate. This would correspond to a fall from 1.4% to 0.42%.
  4. Pretty easy so far on the logic, but now for the core question of the day: If there are no safety issues, can these data in one orthopedic procedure be generalized to other orthopedic procedures?
  5. On this point, the FDA briefing book notes that “Pfizer states that while the rates of invasive S. aureus disease across other elective orthopedic surgical populations are significant, they are low (~0.25% to ~0.5% within 90 days of surgery). Therefore, Pfizer states that conducting a randomized, placebo-controlled clinical endpoint efficacy trial that includes other elective orthopedic surgical populations would make the conduct of such a trial operationally impractical.”
  6. I agree here! My simple man’s sample size calculations quickly take me from the already substantial ~1,300/arm of the current study to sizes beyond 10-20,000 per arm.

Absolutely fascinating and I am delighted to see FDA and Pfizer bringing this great question into a public forum: a path forward in non-geologic time with non-infinite sample sizes is going to be needed if want to have more than a handful of tools of this type.

The FDA briefing book is excellent and I commend it to you … it provides a good summary of past (failed) efforts in this area as well as further details on the key question to be discussed.

All best wishes, –jr

John H. Rex, MD | Chief Medical Officer, F2G Ltd. | Expert-in-Residence, Wellcome Trust. Follow me on Twitter: @JohnRex_NewAbx. See past newsletters and subscribe for the future: http://amr.solutions/blog/

Upcoming meetings of interest to the AMR community:

Share

Fireside Chat with BARDA’s Branch Chief for Antimicrobials

Note: Be sure to take advantage of the BARDA Industry Day(s) event that occurs Monday-Tuesday of this coming week … see newsletter and forward calendar for details. Dear All, In what could be called Part 2 of Excellent 2023 ASM/ESCMID Talks (read the newsletter on Jen Cohen’s talk on how manufacturing underpins both access and

Japan Pulls for Pandemic Preparedness: Nikkei FT Conference

Dear All, As we discussed in the 5 Nov 2023 “Pulling for Pandemic Preparedness” newsletter, AMR is a global threat: resistance in one part of the world can suddenly appear in your hospital. As an example of that sort of threat, Jason Gale’s 30 Oct 2023 newsletter entitled “Untreatable Typhoid Should Make You Worry About Poop”

Pulling for Pandemic Preparedness

Dear All, This evening I’d like to bring together several relatively recent reports and note how all of them focus in one way or another on Pulling for Pandemic Preparedness … perhaps we can call this the Rule of 3 Ps. And as an aside, I’ll note that I learned the Rule of 4 Ps

PACE: A new £30m fund for AMR innovation

Dear All, Exciting additional news merits two newsletters in one day! I’ll keep it brief and quote directly from the website: “Innovate UK, LifeArc, and Medicines Discovery Catapult (MDC) have joined forces to create PACE (Pathways to Antimicrobial Clinical Efficacy), a £30 million initiative supporting early-stage innovation against antimicrobial resistance (AMR) to save lives. PACE has today (19 October 2023) announced

Scroll to Top